ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance

被引：98

作者：

Orme, Jacob J. ^{[1
]}

Jazieh, Khalid A. ^{[2
,3
]}

Xie, Tiancheng ^{[2
]}

Harrington, Susan ^{[2
]}

Liu, Xin ^{[2
]}

Ball, Matthew ^{[4
]}

Madden, Benjamin ^{[5
]}

Charlesworth, M. Cristine ^{[5
]}

Azam, Tariq U. ^{[6
]}

Lucien, Fabrice ^{[2
,7
]}

Wootla, Bharath ^{[8
]}

Li, Yanli ^{[2
,3
]}

Villasboas, Jose Caetano ^{[9
]}

Mansfield, Aaron S. ^{[1
]}

Dronca, Roxana S. ^{[10
]}

Dong, Haidong ^{[3
,7
]}

机构：

[1] Mayo Clin, Div Med Oncol, Rochester, MN USA

[2] Mayo Clin, Dept Urol, Rochester, MN USA

[3] Cleveland Clin, Dept Internal Med, Cleveland, OH 44106 USA

[4] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[5] Mayo Clin, Prote Core, Rochester, MN USA

[6] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA

[7] Mayo Clin, Dept Immunol, Rochester, MN USA

[8] Mayo Clin, Ctr Clin & Translat Sci, Rochester, MN USA

[9] Mayo Clin, Div Hematol, Rochester, MN USA

[10] Mayo Clin, Dept Internal Med, Div Hematol Oncol, Jacksonville, FL 32224 USA

来源：

ONCOIMMUNOLOGY | 2020年 / 9卷 / 01期

关键词：

PD-1; resistance; checkpoint inhibitor resistance; sPD-L1; ADAM10; ADAM17; DEATH LIGAND 1; CIRCULATING PD-L1; GASTRIC-CANCER; EXPRESSION; PROGRESSION; SURVIVAL; HETEROGENEITY; PROGNOSIS; MIGRATION; LEVEL;

D O I：

10.1080/2162402X.2020.1744980

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10- and ADAM17-mediated resistance to PD-(L)1 inhibitors. ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles. This cleavage produces an active sPD-L1 fragment that induces apoptosis in CD8 + T cells and compromises the killing of tumor cells by CD8 + T cells. Reduced tumor site PD-L1 protein-to-mRNA ratios predict poor outcomes and are correlated with elevated ADAM10 and ADAM17 expression in multiple cancers. These results may explain the discordance between PD-L1 immunohistochemistry and PD-(L)1 inhibitor response. Thus, including ADAM10 and ADAM17 tissue staining may improve therapy selection. Furthermore, treatment with an ADAM10/ADAM17 inhibitor may abrogate PD-(L)1 inhibitor resistance and improve clinical responses to PD-(L)1 immunotherapy.

引用

页数：11

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